Leveraging genetic predictors of factor XI levels to anticipate results from clinical trials
Iyas Daghlas, Dipender Gill
Abstract
Abstract Background Factor XI (FXI) is a promising therapeutic target for the prevention of thrombotic disease without increasing bleeding risk. Methods We performed Mendelian randomization (MR) analyses to investigate the association of genetically predicted reductions in FXI levels with risk of venous thromboembolism, ischemic stroke, bleeding outcomes, and lifespan. Results Genetically predicted reductions in FXI levels were associated with lower risk of ischemic stroke (odds ratio per 1 standard deviation (SD) lower serum FXI 0.90, 95% confidence interval 0.87–0.93, p = 1.59 × 10 −11 ), and venous thromboembolism (0.54, 0.49–0.59, p = 2.13 × 10 −39 ) but did not associate with increased bleeding risk ( p > 0.16). Genetically predicted reductions in serum FXI levels associated with longer lifespan (0.37 years per 1 SD lower serum FXI, 0.13–0.61, p = 0.003). Conclusions These genetic data support FXI as a potentially efficacious and safe therapeutic target and anticipate positive results from ongoing phase 3 clinical trials.